medRxiv preprint doi: https://doi.org/10.1101/2021.07.22.21261005; this version posted July 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Systematic Review and Meta-analysis of Eculizumab, Inebilizumab, Tocilizumab, and Satralizumab for Neuromyelitis Optica Running head: Neuromyelitis Optica Rajan Chamlagain1 Sangam Shah2 Suman Gaire3 Anuj Krishna Paudel4 Krishna Dahal2 Bipin kandel1 Roman Dhital1 Basanta Sharma Paudel1 Sandesh Dhakal1 Madan Basnet1 1Department of Internal Medicine, Tribhuvan University Teaching Hospital, Maharajgunj, 44600, Nepal 2Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University, Maharajgunj, Kathmandu, 44600, Nepal 3Department of Emergency Medicine, Palpa Hospital, Palpa, 32500, Nepal 4Department of ICU, Metrocity Hospital and Research center, Kathmandu, 44600, Nepal Corresponding author Sangam Shah Maharajgunj Medical Campus, Institute of Medicine Tribhuvan University Maharajgunj, Kathmandu, Nepal, 44600 Email: [email protected] Number of characters in the title and running head: 120 & 20 Number of words in the abstract, and the body of the manuscript (not including abstract or references, figure legends, etc.): 197 & 4581 Number of figures and tables: 7 & 2 Abstract Neuromyelitis optica is rare, autoimmune-mediated inflammation and demyelination of the central nervous system with a prevalence of 1-2 persons per 100,000 populations. We aim to generate a head-to-head comparison of these drugs with appropriate evidence to guide future trials and treatment guidelines in a patient with recurrent attacks of NMO. We searched the databases like PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase for studies published prior to April 2021 using the keywords. Over all 929 patients from 11 different publications were included in the study. Five studies were included for quantitative synthesis. Pooling of studies showed significant mean reduction of ARR in the monoclonal antibody group (-0.26 [-0.35, -0.17], P <0.00001, I2=0%) and the mean difference in EDSS score from baseline in monoclonal antibodies was - NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.07.22.21261005; this version posted July 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . 0.23(95% CI [-0.43, -0.03], P=0.02, I2=0%). There was no significant difference in frequency of total reported adverse events between monoclonal antibody and the comparator arm (RR: 1.01 [0.95, 1.07], P=0.74, I2=14%). Our findings, particularly seen from the context of a few RCTs, support the pursuit of larger, multi-center RCTs that evaluate the effectiveness of each of the currently available monoclonal antibodies and better describe their adverse risk profile. Introduction Neuromyelitis optica is a rare, autoimmune-mediated inflammation and demyelination of the central nervous system with a prevalence of 1-2 persons per 100,000 populations.1,2 It predominately affects women in the ratio of 9:1.3 NMO is a monophasic or relapsing-remitting disorder predominantly characterized by optic neuritis and transverse myelitis.4 Optic nerve involvement presents with blindness or vision loss, motor impairment, sensory disorder, urination/defecation function disturbance, and vomiting due to the attack of the spinal cord, brain stem involvement resulting in intractable nausea are some main features of a patient with NMOSD.5–8 Transverse myelitis presents with longitudinally extensive spinal cord lesions; a tendency to spare the brain, but when the brain is affected, the presence of magnetic resonance imaging (MRI) lesions is atypical for MS; and frequent association with seropositivity for NMO IgG (IgG antibody to aqua-porin-4). The key marker in NMOSD is an aquaporin-4 antibody (AQP4-Ab) and accounts for 80% of NMOSD cases.9 Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) discovered recently is another biomarker and is found in 4-11% NMOSD patients but does not co-exist with AQP4-Ab seropositivity.10 The pathophysiologic process of NMO is complex involving B cell-mediated production of pathological autoantibody, immunoglobulin G (IgG) which mainly targets the astrocyte water channel aquaporin-4 (AQP4).11,12 AQP4-IgG binds to astrocytic AQP4 and triggers classical complement cascade activation, promotes granulocytic and lymphocytic infiltration which will then combine to damage neural tissues.13 IL-6 plays a pivotal role in driving the disease activity by stimulating AQP4-IgG secretion and plasmablast survival, disrupting blood-brain barrier integrity and production of proinflammatory T-lymphocyte and their differentiation and activation.14 IL-6 levels are elevated in the serum and cerebrospinal fluid of patients with NMO.14,15 Hence, the main goals in treatment of NMO include acute symptomatic therapy and long-term prevention of relapses. For acute management, corticosteroids and/or plasmapheresis are used while drugs like rituximab, mycophenolate, and azathioprine are recommended for maintenance therapy.16–18 These drugs might be effective in preventing relapses but the prolonged or even lifelong immunosuppression often leads to inevitable adverse effects. Hence, newer therapies (eculizumab, inebilizumab, tocilizumab, and satralizumab) are proposed to prevent future attacks in patients of neuromyelitis optica.2,19 These therapies possess medRxiv preprint doi: https://doi.org/10.1101/2021.07.22.21261005; this version posted July 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . different targets within the immune pathogenic process and hence, can alter the outcome in patient of neuromyelitis optica.2 Eculizumab inhibits the classical complement system and formation of membrane attack complex thus, inhibiting neuronal injury.20 Inebilizumab is another humanized, binds to the B-cell surface antigen CD19 that identifies and depletes a wider range of lymphocytes exclusively from the B-cell lineage.21 In contrast, satralizumab and tocilizumab are humanized monoclonal antibody that binds to IL-6 receptors and inhibits the IL-6 signalling pathways involved in inflammation.22,23 However, these drugs are still not compared based on decreased relapse risk, Annualized Relapse Rate (ARR) ratio, improve Expanded Disability Status Scale (EDSS) score, serious adverse events, and mortality. Therefore, in this study, we aim to generate a head-to-head comparison of these drugs with appropriate evidence to guide future trials and treatment guidelines in a patient with recurrent attacks of NMO. Literature Review Methods This meta-analysis confirms to standard guidelines and is written in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) statement24. (CRD42021255886) Study selection We performed comprehensive and systematic literature search for all studies about the use of eculizumab, inebilizumab, satralizumab, and tocilizumab to treat NMOSD patients. We searched the databases like PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase for studies published prior to April 2021 using the keywords ‘neuromyelitis optic spectrum disorders’ or ‘NMOSD’ or ‘aquaporin 4 antibody’, or ‘devic’s disease, or ‘monoclonal antibody’ and the drug names ‘tocilizumab’, ‘eculizumab’, ‘inebilizumab’, and ‘satralizumab’. We also searched the reference lists of all included studies and any associated review articles to identify any relevant studies that were missed in the initial search. The detail study of study selection is shown by flowchart in Fig. 1. Two reviewers (SS and RC) independently screened the retrieved articles and obtained the full texts of all the articles that met the predefined selection criteria. Any discrepancies between reviews were solved by discussion with the third author (BSP, KD, SG, AKP). We read full studies after identifying all the articles and screening the abstracts. Ultimately, twelve studies met the inclusion criteria and were included in the review (Supplemetal table 1). Inclusion and Exclusion criteria We included the studies that fulfilled the following criteria: (1) The study population composed of NMOSD patients with any of its types (2) Treatment with tocilizumab, medRxiv preprint doi: https://doi.org/10.1101/2021.07.22.21261005; this version posted July 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . or eculizumab, or inebilizumab, or satralizumab; (3) The articles that were available in English language and was of human. The exclusion criteria were as follows: (1) case reports and studies that included less than ten patients; (2) studies that were published in other languages (3) data presented only